Journal
EMBO JOURNAL
Volume 30, Issue 22, Pages 4571-4585Publisher
WILEY
DOI: 10.1038/emboj.2011.325
Keywords
keratinocytes; Notch; p63; squamous cell carcinoma; tumour suppression
Categories
Funding
- NIH [AR39190, AR054856]
- European Union [LSHB-CT-2005-019067]
- Swiss National Foundation [3100A0-122281/1]
- Oncosuisse [02361-02-2009]
- Olga-Mayenfisch-Stiftung
- Wellcome Trust [082868]
- MRC [G 0901539]
- MRC [G0901539] Funding Source: UKRI
- Medical Research Council [G0901539] Funding Source: researchfish
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While the pro-differentiation and tumour suppressive functions of Notch signalling in keratinocytes are well established, the underlying mechanisms remain poorly understood. We report here that interferon regulatory factor 6 (IRF6), an IRF family member with an essential role in epidermal development, is induced in differentiation through a Notch-dependent mechanism and is a primary Notch target in keratinocytes and keratinocyte-derived SCC cells. Increased IRF6 expression contributes to the impact of Notch activation on growth/differentiation-related genes, while it is not required for induction of 'canonical' Notch targets like p21 WAF1/Cip1, Hes1 and Hey1. Down-modulation of IRF6 counteracts differentiation of primary human keratinocytes in vitro and in vivo, promoting ras-induced tumour formation. The clinical relevance of these findings is illustrated by the strikingly opposite pattern of expression of Notch1 and IRF6 versus epidermal growth factor receptor in a cohort of clinical SCCs, as a function of their grade of differentiation. Thus, IRF6 is a primary Notch target in keratinocytes, which contributes to the role of this pathway in differentiation and tumour suppression. The EMBO Journal (2011) 30, 4571-4585. doi:10.1038/emboj.2011.325; Published online 9 September 2011 Subject Categories: signal transduction; molecular biology of disease
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